One of the reasons that it is difficult to treat individuals who are addicted to drugs like heroin is that withdrawal is associated with intense negative emotions. If we understood the neurobiology of withdrawal induced negative emotionality, this might provide an avenue for novel and more successful prevention/intervention treatments for drug abuse. This proposal will examine the neural substrates of opiate dependence using an "acute" dependence paradigm, in which withdrawal is assessed following a single opiate exposure. Acute dependence paradigms are especially well suited for studying the neuroadaptive mechanisms involved in the incipient stages of drug dependence. Potentiation of the startle reflex, which is already widely used in studies of anxiety and fear, will serve as an objective, reliable, and graded measure of withdrawal-induced negative affect. The proposed studies will examine the role of receptors of the neuropeptide corticotropin releasing factor (CRF) in the brain in acute opiate dependence. First, activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is mediated by release of CRF from the hypothalamus, will be evaluated during withdrawal from acute morphine. Second, the effects of blockade of HPA axis activation on acute opiate dependence will be determined. Third, the role of CRF receptor activation in acute dependence will be investigated, through intracranial microinfusion of a selective CRF receptor antagonist prior to the onset of withdrawal. These studies will lay the groundwork for further characterization of the neural substrates of acute opiate dependence, working towards the long-term goal of developing novel therapeutic approaches for treating drug dependence. [unreadable] [unreadable] [unreadable]